Genetic and epigenetic alterations of myeloproliferative disorders
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PROGRESS IN HEMATOLOGY
Genetic and epigenetic alterations in hematopoietic malignancies
Genetic and epigenetic alterations of myeloproliferative disorders Jelena D. Milosevic • Robert Kralovics
Received: 24 October 2012 / Revised: 27 November 2012 / Accepted: 27 November 2012 / Published online: 12 December 2012 Ó The Japanese Society of Hematology 2012
Abstract The classical BCR–ABL negative myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia, and primary myelofibrosis are clonal hematopoietic disorders characterized by excessive production of terminally differentiated myeloid cells. In MPN patients, the disease can progress to secondary myelofibrosis or acute myeloid leukemia. Clonal hematopoiesis, disease phenotype, and progression are caused by somatically acquired genetic lesions of genes involved in cytokine signaling, RNA splicing, as well as epigenetic regulation. This review provides an overview of point mutations and cytogenetic lesions associated with MPN and addresses the role of these somatic lesions in MPN disease progression. Keywords Myeloproliferative disorder Polycythemia vera Essential thrombocythemia Primary myelofibrosis
Introduction Myeloproliferative neoplasms (MPN) are characterized by clonal expansion of terminally differentiated myeloid cells. According to the 2008 WHO classification, MPNs include polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myeloid leukemia
J. D. Milosevic R. Kralovics (&) CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT25.3, 1090 Vienna, Austria e-mail: [email protected] R. Kralovics Division of Hematology and Blood Coagulation, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
(CML), chronic neutrophilic leukemia, mastocytosis, and chronic eosinophilic leukemia not otherwise specified, as well as unclassifiable MPN [1]. The first four disease entities are also known as ‘‘classical’’ MPNs. Since CML is characterized by the oncogenic fusion of the BCR and ABL genes, PV, ET, and PMF are commonly known as Philadelphia-chromosome negative or BCR–ABL negative MPNs. Despite their phenotypic diversity, all MPNs exhibit clonal hematopoiesis driven by acquired mutations. The most famous example of such a driver mutation is the BCR–ABL fusion oncogene causing CML. The discovery of the BCR–ABL fusion has made molecular diagnosis as well as therapeutic management of CML possible. In 2005, a somatic mutation in the JAK2 gene was identified in the ‘‘classical’’ MPNs with similar significance as BCR–ABL in CML. The MPN-associated JAK2 mutation (V617F) has been found in over 90 % of PV cases and in about 50–60 % of ET and PMF [2–5]. The V617F mutation is located in exon 14 of JAK2, but various exon 12 mutations have also been described in PV [6, 7]. Mutational analysis of JAK2 has greatly aided the diagnosis of the ‘‘classical’’ MPNs, and there are several Janus kinase 2 (JAK2) kinase inhibitors at vario
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